We have identified and abstracted medical records and obtained detailed laboratory and pharmacy data for over 800 incident cases of renal cell carcinoma (RCC) diagnosed at Kaiser Permanente Northwest (KPNW) and Group Health Cooperative of the Puget Sound (GHC) to study a variety of medical, pharmacologic, and behavioral factors in relation to the incidence of RCC. In this grant application, we propose to pilot-test the addition of a molecular-biological component to our ongoing research activities using archived paraffin-embedded, formalin-fixed tissue blocks from primary RCC tumors. This expansion is motivated by an emerging literature suggesting the importance of genetic abnormalities and markers of proliferation as prognostic indicators of RCC and implicating environmental factors in genetic change. We propose to analyze molecular alterations and tumor histological characteristics in a subset of 100 KPNW cases in order to test preliminary hypotheses on the molecular epidemiology of RCC and to evaluate the feasibility of conducting molecular studies on our entire case population. With these data, we will explore the following questions: 1) Are subgroups of RCC characterized by von Hippel-Lindau (VHL) gene mutations, p53 mutations, and other genetic alterations, as well as cytokines, growth factors and markers of proliferation, associated with putative risk factors for RCC including cigarette smoking, obesity, hypertension, diabetes, and thiazide diuretic use? 2) Are these somatic mutations and markers of proliferative activity modified by patient gender, cigarette smoking status, obesity, hypertension, and diabetes? This study is likely to provide new knowledge concerning the etiology and prognosis of RCC, as few previous molecular studies of this cancer have evaluated potential associations between tumor characteristics and other medical, behavior or environmental factors.